The impact of right atrial pressure on outcomes in patients undergoing TIPS, an ALTA group study.

BACKGROUND AND AIMS: Single-center studies in patients undergoing TIPS suggest that elevated right atrial pressure (RAP) may influence survival. We assessed the impact of pre-TIPS RAP on outcomes using the Advancing Liver Therapeutic Approaches (ALTA) database. APPROACH AND RESULTS: Total 883 patients in ALTA multicenter TIPS database from 2010 to 2015 from 9 centers with measured pre-TIPS RAP were included. Primary outcome was mortality. Secondary outcomes were 48-hour post-TIPS complications, post-TIPS portal hypertension complications, and post-TIPS inpatient admission for heart failure. Adjusted Cox Proportional hazards and competing risk model with liver transplant as a competing risk were used to assess RAP association with mortality. Restricted cubic splines were used to model nonlinear relationship. Logistic regression was used to assess RAP association with secondary outcomes.Pre-TIPS RAP was independently associated with overall mortality (subdistribution HR: 1.04 per mm Hg, 95% CI, 1.01, 1.08, p =0.009) and composite 48-hour complications. RAP was a predictor of TIPS dysfunction with increased odds of post-90-day paracentesis in outpatient TIPS, hospital admissions for renal dysfunction, and heart failure. Pre-TIPS RAP was positively associated with model for end-stage liver disease, body mass index, Native American and Black race, and lower platelets. CONCLUSIONS: Pre-TIPS RAP is an independent risk factor for overall mortality after TIPS insertion. Higher pre-TIPS RAP increased the odds of early complications and overall portal hypertensive complications as potential mechanisms for the mortality impact.

Change in Platelet Count after Transjugular Intrahepatic Portosystemic Shunt Creation: An Advancing Liver Therapeutic Approaches (ALTA) Group Study.

PURPOSE: To evaluate recovery of platelet count after transjugular intrahepatic portosystemic shunt (TIPS) creation and patient factors predicting platelet recovery after TIPS creation. MATERIALS AND METHODS: Adults with cirrhosis who underwent TIPS creation at 9 U.S. hospitals from 2010 to 2015 were included in this retrospective analysis. Change in platelets from before TIPS to 4 months after TIPS creation was characterized. Logistic regression was used to assess factors associated with top quartile percentage platelet increase after TIPS. Subgroup analyses were performed among patients with a pre-TIPS platelet count of ≤50 ×109/L. RESULTS: A total of 601 patients were included. The median absolute change in platelets was 1 × 109/L (-26 × 109/L to 25 × 109/L). Patients with top quartile percent platelet increase experienced ≥32% platelet increase. In multivariable analysis, pre-TIPS platelet counts (odds ratio [OR], 0.97 per 109/L; 95% CI, 0.97-0.98), age (OR, 1.24 per 5 years; 95% CI, 1.10-1.39), and pre-TIPS model for end-stage liver disease (MELD) scores (OR, 1.06 per point; 95% CI, 1.02-1.09) were associated with top quartile (≥32%) platelet increase. Ninety-four (16%) patients had a platelet count of ≤50 × 109/L before TIPS. The median absolute platelet change was 14 × 109/L (2 × 109/L to 34 × 109/L). Fifty-four percent of patients in this subgroup were in the top quartile for platelet increase. In multivariable logistic regression, age (OR, 1.50 per 5 years; 95% CI, 1.11-2.02) was the only factor associated with top quartile platelet increase in this subgroup. CONCLUSIONS: TIPS creation did not result in significant platelet increase, except among patients with a platelet count of ≤50 × 109/L before TIPS. Lower pre-TIPS platelet counts, older age, and higher pre-TIPS MELD scores were associated with top quartile (≥32%) platelet increase in the entire cohort, whereas only older age was associated with this outcome in the patient subset with a pre-TIPS platelet count of ≤50 × 109/L.

Outcomes After TIPS for Ascites and Variceal Bleeding in a Contemporary Era-An ALTA Group Study.

INTRODUCTION: Advances in transjugular intrahepatic portosystemic shunt (TIPS) technology have led to expanded use. We sought to characterize contemporary outcomes of TIPS by common indications. METHODS: This was a multicenter, retrospective cohort study using data from the Advancing Liver Therapeutic Approaches study group among adults with cirrhosis who underwent TIPS for ascites/hepatic hydrothorax (ascites/HH) or variceal bleeding (2010-2015). Adjusted competing risk analysis was used to assess post-TIPS mortality or liver transplantation (LT). RESULTS: Among 1,129 TIPS recipients, 58% received TIPS for ascites/HH and 42% for variceal bleeding. In patients who underwent TIPS for ascites/HH, the subdistribution hazard ratio (sHR) for death was similar across all Model for End-Stage Liver Disease Sodium (MELD-Na) categories with an increasing sHR with rising MELD-Na. In patients with TIPS for variceal bleeding, MELD-Na ≥20 was associated with increased hazard for death, whereas MELD-Na ≥22 was associated with LT. In a multivariate analysis, serum creatinine was most significantly associated with death (sHR 1.2 per mg/dL, 95% confidence interval [CI] 1.04-1.4 and 1.37, 95% CI 1.08-1.73 in ascites/HH and variceal bleeding, respectively). Bilirubin and international normalized ratio were most associated with LT in ascites/HH (sHR 1.23, 95% CI 1.15-1.3; sHR 2.99, 95% CI 1.76-5.1, respectively) compared with only bilirubin in variceal bleeding (sHR 1.06, 95% CI 1.00-1.13). DISCUSSION: MELD-Na has differing relationships with patient outcomes dependent on TIPS indication. These data provide new insights into contemporary predictors of outcomes after TIPS.

Nonalcoholic Fatty Liver Disease and Diabetes Mellitus Are Associated With Post-Transjugular Intrahepatic Portosystemic Shunt Renal Dysfunction: An Advancing Liver Therapeutic Approaches Group Study.

Transjugular intrahepatic portosystemic shunt (TIPS) is an effective intervention for portal hypertensive complications, but its effect on renal function is not well characterized. Here we describe renal function and characteristics associated with renal dysfunction at 30 days post-TIPS. Adults with cirrhosis who underwent TIPS at 9 hospitals in the United States from 2010 to 2015 were included. We defined "post-TIPS renal dysfunction" as a change in estimated glomerular filtration rate (ΔeGFR) ≤-15 and eGFR ≤ 60 mL/min/1.73 m2 or new renal replacement therapy (RRT) at day 30. We identified the characteristics associated with post-TIPS renal dysfunction by logistic regression and evaluated survival using adjusted competing risk regressions. Of the 673 patients, the median age was 57 years, 38% of the patients were female, 26% had diabetes mellitus, and the median MELD-Na was 17. After 30 days post-TIPS, 66 (10%) had renal dysfunction, of which 23 (35%) required new RRT. Patients with post-TIPS renal dysfunction, compared with those with stable renal function, were more likely to have nonalcoholic fatty liver disease (NAFLD; 33% versus 17%; P = 0.01) and comorbid diabetes mellitus (42% versus 24%; P = 0.001). Multivariate logistic regressions showed NAFLD (odds ratio [OR], 2.04; 95% confidence interval [CI], 1.00-4.17; P = 0.05), serum sodium (Na; OR, 1.06 per mEq/L; 95% CI, 1.01-1.12; P = 0.03), and diabetes mellitus (OR, 2.04; 95% CI, 1.16-3.61; P = 0.01) were associated with post-TIPS renal dysfunction. Competing risk regressions showed that those with post-TIPS renal dysfunction were at a higher subhazard of death (subhazard ratio, 1.74; 95% CI, 1.18-2.56; P = 0.01). In this large, multicenter cohort, we found NAFLD, diabetes mellitus, and baseline Na associated with post-TIPS renal dysfunction. This study suggests that patients with NAFLD and diabetes mellitus undergoing TIPS evaluation may require additional attention to cardiac and renal comorbidities before proceeding with the procedure.

Outcomes of Liver Transplantation Among Older Recipients With Nonalcoholic Steatohepatitis in a Large Multicenter US Cohort: the Re-Evaluating Age Limits in Transplantation Consortium.

The liver transplantation (LT) population is aging, with the need for transplant being driven by the growing prevalence of nonalcoholic steatohepatitis (NASH). Older LT recipients with NASH may be at an increased risk for adverse outcomes after LT. Our objective is to characterize outcomes in these recipients in a large multicenter cohort. All primary LT recipients ≥65 years from 2010 to 2016 at 13 centers in the Re-Evaluating Age Limits in Transplantation (REALT) consortium were included. Of 1023 LT recipients, 226 (22.1%) were over 70 years old, and 207 (20.2%) had NASH. Compared with other LT recipients, NASH recipients were older (68.0 versus 67.3 years), more likely to be female (47.3% versus 32.8%), White (78.3% versus 68.0%), Hispanic (12.1% versus 9.2%), and had higher Model for End-Stage Liver Disease-sodium (21 versus 18) at LT (P < 0.05 for all). Specific cardiac risk factors including diabetes with or without chronic complications (69.6%), hypertension (66.3%), hyperlipidemia (46.3%), coronary artery disease (36.7%), and moderate-to-severe renal disease (44.4%) were highly prevalent among NASH LT recipients. Graft survival among NASH patients was 90.3% at 1 year and 82.4% at 3 years compared with 88.9% at 1 year and 80.4% at 3 years for non-NASH patients (log-rank P = 0.58 and P = 0.59, respectively). Within 1 year after LT, the incidence of graft rejection (17.4%), biliary strictures (20.9%), and solid organ cancers (4.9%) were comparable. Rates of cardiovascular (CV) complications, renal failure, and infection were also similar in both groups. We observed similar posttransplant morbidity and mortality outcomes for NASH and non-NASH LT recipients. Certain CV risk factors were more prevalent in this population, although posttransplant outcomes within 1 year including CV events and renal failure were similar to non-NASH LT recipients.

Vemurafenib-induced granulomatous hepatitis.

Vemurafenib (Zelboraf; Genentech, CA) is a highly effective oral chemotherapy agent for patients with metastatic melanoma who carry the BRAF V600E mutation. Side effects of this protein kinase inhibitor (PKI) include arthralgia, rash, and fatigue, which are reported in up to one third of treated patients. Mild abnormalities in liver biochemistries were reported with vemurafenib use in 30% of subjects, 11% developed severe laboratory abnormalities, and acute liver failure has been reported (Table ). Herein, a case of severe vemurafenib-induced granulomatous hepatitis leading to chronic cholestasis is reported along with a review of the hepatotoxicity of other PKIs.

Opioid and opioid substitution therapy in liver transplant candidates: A survey of center policies and practices.

This national survey sought to determine the practices and policies pertaining to opioid and opioid substitution therapy (OST) use in the selection of liver transplant (LT) candidates. Of 114 centers, 61 (53.5%) responded to the survey, representing 49.2% of the LT volume in 2016. Only two programs considered chronic opioid (1 [1.6%]) or OST use (1 [1.6%]) absolute contraindications to transplant, while 63.9% and 37.7% considered either one a relative contraindication, respectively. The majority of programs did not have a written policy regarding chronic opioid use (73.8%) or OST use (78.7%) in LT candidates. Nearly half (45.9%) of centers agreed that there should be a national consensus policy addressing opioid and OST use. The majority of responding LT centers did not consider opioid or OST use in LT candidates to be absolute contraindications to LT, but there was significant variability in center practices. These surveys also demonstrated a lack of written policies in the assessment of the candidacy of such patients. The results of our survey identify an opportunity to develop a national consensus statement regarding opioid and OST use in LT candidates to bring greater uniformity and equity into the selection of LT candidates.

Alcoholic hepatitis: current management.

Alcoholic hepatitis is an acute manifestation of alcoholic liver disease with mortality as high as 40-50% in severe cases. Patients usually have a history of prolonged alcohol abuse with or without a known history of liver disease. Although there is significant range in severity at presentation, patients with severe alcoholic hepatitis typically present with anorexia, fatigue, fever, jaundice, and ascites. The use of either pentoxifylline or corticosteroids in those with severe disease (Maddrey's discriminate function >32) has significant mortality benefit. The addition of N-acetylcysteine to corticosteroids decreases the incidences of hepatorenal syndrome, infection, and short-term mortality, but does not appear to significantly affect 6-month mortality. Nutritional support with high-calorie, high-protein diet is recommended in all patients screening positive for malnutrition. Liver transplantation for a highly selected group of patients with severe alcoholic hepatitis may be an option in the future, but is not currently recommended or available at most transplant institutions.

Cholestasis Linked to Bodybuilding Supplements: Exploring the Risks of Contamination.

Drug-induced liver injury resulting from herbal and dietary supplement use is increasingly common and underrecognized. We report a case of a 34-year-old male recreational bodybuilder who presented with muscle cramping, fatigue, and diffuse itching in the setting of bodybuilding supplement use. Labs showed cholestatic liver injury, and liver biopsy revealed bland cholestasis and sinusoidal dilation. He was diagnosed with anabolic-androgenic steroid-induced liver injury. He was symptomatically managed with plasmapheresis for debilitating pruritus. This case highlights drug-induced liver injury as a complication of bodybuilding supplement use containing unlabeled anabolic-androgenic steroids. Sports medicine providers should inquire on herbal and dietary supplement use and be aware of potential contaminants.

Severe Cholestatic Hepatitis Secondary to SARS-CoV-2.

Liver injury is a common manifestation of coronavirus disease 2019 (COVID-19), with most injuries manifesting as transient mild hepatocellular injury. Cholestatic injury occurs less commonly and is typically mild. Severe cholestatic injury is rare, with only 4 cases reported in the literature. We present a 70-year-old woman with no known liver disease who presented with severe COVID-19 and developed severe cholestatic hepatitis. A liver biopsy was performed demonstrating bile duct injury, uncommonly reported in patients with COVID-19. This complication needs greater awareness because it has been known to cause progressive liver disease requiring transplantation.

Plasmapheresis for Pembrolizumab-Induced Hepatitis in a Patient with Squamous Cell Carcinoma and Prior Orthotopic Liver Transplantation.

Checkpoint inhibitor therapy with monoclonal antibodies against programmed cell death protein 1 (PD1) has been implemented in the treatment of numerous malignancies. Pembrolizumab is one such medication. While severe toxicities are very rare, mild immune-mediated reactions with a variety of end organ injuries are among the most commonly encountered adverse events attributed to these medications. Acute liver injury manifesting as biochemical abnormalities with or without synthetic dysfunction is one such potential adverse reaction. Rarely, a relatively severe hepatitis can occur. While such severe adverse events are often successfully managed with systemic corticosteroids and drug discontinuation, our patient was refractory to standard management. We present a case of pembrolizumab-induced hepatitis in a patient with squamous cell carcinoma and prior orthotopic liver transplantation. Through a combination of serial plasmapheresis and intravenous immunoglobulin(IVIG) infusion, the patient's hepatitis resolved as evidenced by virtual normalization of his liver indices. This illustrates the effectiveness of a relatively novel treatment strategy for this rare side effect of checkpoint inhibitor antineoplastic therapy.

Transcriptome changes in stages of non-alcoholic fatty liver disease.

BACKGROUND: Non-alcoholic fatty liver disease (NAFLD) is the most common chronic liver disease in the United States and globally. The currently understood model of pathogenesis consists of a 'multiple hit' hypothesis in which environmental and genetic factors contribute to hepatic inflammation and injury. AIM: To examine the genetic expression of NAFLD and non-alcoholic steatohepatitis (NASH) tissue samples to identify common pathways that contribute to NAFLD and NASH pathogenesis. METHODS: We employed the Search Tag Analyze Resource for Gene Expression Omnibus platform to search the The National Center for Biotechnology Information Gene Expression Omnibus to elucidate NAFLD and NASH pathology. For NAFLD, we conducted meta-analysis of data from 58 NAFLD liver biopsies and 60 healthy liver biopsies; for NASH, we analyzed 187 NASH liver biopsies and 154 healthy liver biopsies. RESULTS: Our results from the NAFLD analysis reinforce the role of altered metabolism, inflammation, and cell survival in pathogenesis and support recently described contributors to disease activity, such as altered androgen and long non-coding RNA activity. The top upstream regulator was found to be sterol regulatory element binding transcription factor 1 (SREBF1), a transcription factor involved in lipid homeostasis. Downstream of SREBF1, we observed upregulation in CXCL10, HMGCR, HMGCS1, fatty acid binding protein 5, paternally expressed imprinted gene 10, and downregulation of sex hormone-binding globulin and insulin-like growth factor 1. These molecular changes reflect low-grade inflammation secondary to accumulation of fatty acids in the liver. Our results from the NASH analysis emphasized the role of cholesterol in pathogenesis. Top canonical pathways, disease networks, and disease functions were related to cholesterol synthesis, lipid metabolism, adipogenesis, and metabolic disease. Top upstream regulators included pro-inflammatory cytokines tumor necrosis factor and IL1B, PDGF BB, and beta-estradiol. Inhibition of beta-estradiol was shown to be related to derangement of several cellular downstream processes including metabolism, extracellular matrix deposition, and tumor suppression. Lastly, we found riciribine (an AKT inhibitor) and ZSTK-474 (a PI3K inhibitor) as potential drugs that targeted the differential gene expression in our dataset. CONCLUSION: In this study we describe several molecular processes that may correlate with NAFLD disease and progression. We also identified ricirbine and ZSTK-474 as potential therapy.

Tumor aggressiveness is independent of radiation quality in murine hepatocellular carcinoma and mammary tumor models.

PURPOSE: Estimating cancer risk associated with interplanetary space travel is complicated. Human exposure data to high atomic number, high-energy (HZE) radiation is lacking, so data from low linear energy transfer (low-LET) γ-ray radiation is used in risk models, with the assumption that HZE and γ-ray radiation have comparable biological effects. This assumption has been challenged by reports indicating that HZE radiation might produce more aggressive tumors. The goal of this research is to test whether high-LET HZE radiation induced tumors are more aggressive. MATERIALS AND METHODS: Murine models of mammary and liver cancer were used to compare the impact of exposure to 0.2Gy of 300MeV/n silicon ions, 3 Gy of γ-rays or no radiation. Numerous measures of tumor aggressiveness were assessed. RESULTS: For the mammary cancer models, there was no significant change in the tumor latency or metastasis in silicon-irradiated mice compared to controls. For the liver cancer models, we observed an increase in tumor incidence but not tumor aggressiveness in irradiated mice. CONCLUSION: Tumors in the HZE-irradiated mice were not more aggressive than those arising from exposure to low-LET γ-rays or spontaneously. Thus, enhanced aggressiveness does not appear to be a uniform characteristic of all tumors in HZE-irradiated animals.

Transjugular intrahepatic portosystemic shunt does not independently increase risk of death in high model for end stage liver disease patients.

Physicians often exclude patients with a model for end-stage liver disease (MELD) score ≥ 18 from a transjugular intrahepatic portosystemic shunt (TIPS) procedure due to the concern for higher risk of death. We aimed to determine if TIPS increased the risk of death in these patients. We analyzed the interaction between TIPS and MELD in 106 patients with TIPS and 79 with intractable ascites without TIPS. We performed Cox proportional hazard regression, including both TIPS and MELD as time-dependent covariates together with their interaction, to calculate the impact of TIPS on the risk of death associated with a high MELD score. We found a negative interaction between a high MELD score and a history of TIPS, with potentially important effect sizes. Patients with MELD scores ≥18 had a 51% lower incremental risk of death (lower risk than would be expected from the combined independent risks of MELD and needing/receiving TIPS) associated with TIPS than patients with MELD scores <18 (hazard ratio for TIPS, 0.49; 95% confidence interval, 0.10-2.45) in the first 6 months following TIPS. There was an 80% lower incremental risk of death among patients with a MELD score ≥18 (hazard ratio for TIPS, 0.20; 95% confidence interval, 0.03-1.23) 6 months after the TIPS procedure. Conclusion: Risk of death is associated with underlying disease severity as shown by the MELD score and the need for TIPS, and both history of TIPS and high MELD score independently increased the risk of mortality. However, the risk of death after TIPS was progressively lower than expected as the MELD score increased. (Hepatology Communications 2017;1:460-468).

Liver Transplantation in the Obese Cirrhotic Patient.

Despite the rapidly increasing prevalence of obesity in the transplant population, the optimal management of obese liver transplant candidates remains undefined. Setting strict body mass index cutoffs for transplant candidacy remains controversial, with limited data to guide this practice. Body mass index is an imperfect measure of surgical risk in this population, partly due to volume overload and variable visceral adiposity. Weight loss before transplantation may be beneficial, but it remains important to avoid protein calorie malnutrition and sarcopenia. Intensive lifestyle modifications appear to be successful in achieving weight loss, though the durability of these interventions is not known. Pretransplant and intraoperative bariatric surgeries have been performed, but large randomized controlled trials are lacking. Traditional cardiovascular comorbidities are more prevalent in obese individuals and remain the basis for pretransplant cardiovascular evaluation and risk stratification. The recent US liver transplant experience demonstrates comparable patient and graft survival between obese and nonobese liver transplant recipients, but obesity presents important medical and surgical challenges during and after transplant. Specifically, obesity is associated with an increased incidence of wound infections, wound dehiscence, biliary complications and overall infection, and confers a higher risk of posttransplant obesity and metabolic syndrome-related complications. In this review, we examine current practices in the obese liver transplant population, offer recommendations based on the currently available data, and highlight areas where additional research is needed.

Recommendations for Diagnosis, Referral for Liver Biopsy, and Treatment of Nonalcoholic Fatty Liver Disease and Nonalcoholic Steatohepatitis.

Nonalcoholic fatty liver disease (NAFLD) is the primary cause of chronic liver disease in the United States, afflicting an estimated 80 to 100 million Americans. Nonalcoholic fatty liver disease is a spectrum of liver diseases composed of nonalcoholic fatty liver and nonalcoholic steatohepatitis (NASH). Although nonalcoholic fatty liver has a negligible risk of progression, patients with NASH often develop cirrhosis or hepatocellular carcinoma. Although liver biopsy is required to diagnose NASH, only patients with a high risk of NASH or advanced fibrosis require this evaluation. Despite the high prevalence of NAFLD, well-defined screening recommendations are currently lacking. In this review, suggestions for screening, diagnosis, and initial work-up of NAFLD are given on the basis of established guidelines and recent publications. Proposed drug treatments of NASH are also discussed, highlighting the study outcomes, as well as proposed uses and limitations of these drugs. The literature was searched in PubMed using search terms nonalcoholic fatty liver disease and nonalcoholic steatohepatitis, with filters of "English language." A date range of January 1, 2000, to May 1, 2015, was used for the search. The bibliographies of key references were also searched manually, and seminal publications before the year 2000 were included.

Developing future faculty: a program targeting internal medicine fellows' teaching skills.

INTRODUCTION: The increased demand for clinician-educators in academic medicine necessitates additional training in educational skills to prepare potential candidates for these positions. Although many teaching skills training programs for residents exist, there is a lack of reports in the literature evaluating similar programs during fellowship training. AIM: To describe the implementation and evaluation of a unique program aimed at enhancing educational knowledge and teaching skills for subspecialty medicine fellows and chief residents. SETTING: Fellows as Clinician-Educators (FACE) program is a 1-year program open to fellows (and chief residents) in the Department of Internal Medicine at the University of Iowa. PROGRAM DESCRIPTION: The course involves interactive monthly meetings held throughout the academic year and has provided training to 48 participants across 11 different subspecialty fellowships between 2004 and 2009. PROGRAM EVALUATION: FACE participants completed a 3-station Objective Structured Teaching Examination using standardized learners, which assessed participants' skills in giving feedback, outpatient precepting, and giving a mini-lecture. Based on reviews of station performance by 2 independent raters, fellows demonstrated statistically significant improvement on overall scores for 2 of the 3 cases. Participants self-assessed their knowledge and teaching skills prior to starting and after completing the program. Analyses of participants' retrospective preassessments and postassessments showed improved perceptions of competence after training. CONCLUSION: The FACE program is a well-received intervention that objectively demonstrates improvement in participants' teaching skills. It offers a model approach to meeting important training skills needs of subspecialty medicine fellows and chief residents in a resource-effective manner.